The American Fibromyalgia Syndrome Association

Dextromethorphan (DM) is a cough suppressant that is also an NMDA receptor antagonist. NMDA receptor activation is involved in the perpetuation of chronic pain states and dextromethorphan has been successfully used in the treatment of post herpectic neuralgia (Nelson, Neurology 48:1212, 1997). In the current study we investigated the efficacy of DM in the treatment of fibromyalgia pain.

Patients and Methods: Fifty female fibromyalgia patients (age 49.7 ± 6.1) who were taking a stable dose of tramadol (~200 mg/d) were given an escalating dose of DM (50 mg to 200 mg/d) at a rate increase of 50 mg every 3 days. They were instructed to stabilize the dose either when they achieved a worthwhile improvement in pain or if they experienced unacceptable side effects. Subjects reporting a 25% improvement on a pain VAS were then randomized into a double blind protocol in which they either continued on the same number of DM capsules or took an active placebo (PL) (diphenhydramine 2 mg / capsule - which is the active ingredient in Benadryl). They were instructed to return in 30 days or when their pain level returned to the pre-study level. The primary outcome measure was time to drop out. (VAS stands for visual analog scale, which is a number from zero to ten in perceived pain where ten is the highest level of discomfort.)

Results: Fifty patients entered the study, 2 failed to follow-up. Twenty- eight (58%) experienced a 25% improvement in pain without significant side effects and entered the double blind phase (DB). Reasons for not proceeding to DB were lack of efficacy (#10) and adverse events (#10). The most common adverse events were dizziness, mental fog, nausea and fatigue. Sixteen subjects entered the DM arm (final dose 154± 69 mg/d). One subject in the placebo arm (placebo responder) and 9 subjects in the dextromethorphan arm completed the study (Fischer exact test P=0.018). Overall the DM group of 16 subjects improved their pain VAS by 36% and reported a global improvement of 29%. The DM responders improved their pain VAS by 51% (P<0.0001) and had a global improvement of 49%. The 7 DM non-responders increased their pain VAS by 4% (P=0.7) and reported a global worsening of 8%. The placebo group improved their pain VAS by 7% and reported a global improvement of 0.9%.

Conclusion: Dextromethorphan added to tramadol either does not benefit or is not tolerated by the majority of FM patients. However some 18% of those starting this study experienced a significant and impressive improvement in pain on DM compared to placebo, and most have continued to use supplemental DM. Supplemental dextromethorphan may have a therapeutic role in a small subset of FM patients.

Comments: If you are taking a pain medication (e.g., opioid), then taking a small dose of DM along with this medication could boost its pain relieving powers. DM is available in over-the-counter cough syrups such as DELSYM and it can also be compounded for you with a prescription from your doctor. Dr. Bennett recommends that patients start out with a small dose of DM (less than 50 mg/day) and increase until side effects begin to impact your function. The key is to start at a low dose and work up.

Aims: Thalamic microstimulation activates brain limbic system and evokes acute chest pain without nociception, in patients with recurrent, non-cardiac chest pain and panic disorder (Lenz et al., Nat Med, 1995). We determined if (1) anticipation of acute pain and high arousal feedback evokes pain in the absence of nociception in FM patients with high pain anxiety and NA; and (2) limbic system activation mediates this effect.

Methods: 9 FM patients (4 high NA, 5 low NA) and 9 gender-matched healthy controls (4 high NA, 5 low NA) were studied. NA scores were 1.5 standard deviation (SD) above or 1 SD below normative mean on the Positive and Negative Affect Schedule. Subjects told the 2-day study would measure their responses to potentially painful TENS stimulation although no stimulation actually occurred. Day 1: Subjects completed Pain Anxiety Symptoms Scale (PASS); underwent sham EMG recording at 4 left body sites with preprogrammed EMG feedback indicating low arousal and SPECT brain imaging of regional cerebral blood flow (rCBF). Day 2: Subjects underwent sham TENS stimulation and sham EMG recording at same 4 sites with preprogrammed, high arousal EMG feedback and SPECT brain imaging; and made 4 100mm VAS ratings of pain intensity and unpleasantness at each site immediately before and after sham TENS stimulation. Variables assessed by statistical analysis.

Results: High NA FM patients produced higher PASS scores than all other groups (p's < .05). Only high NA FM patients showed increases in pain intensity and unpleasantness (p's < .03) and right ACC rCBF (P=.03) with sham TENS stimulation. Results for high NA FM patients' Day 2 VAS ratings pre- and post-sham TENS and ACC rCBF at baseline (Day 1) and sham TENS (Day 2) shown below.

Conclusions: (1) Anticipation of acute pain in women with FM, high pain anxiety, and high NA may activate pain memories encoded in ACC and evoke increased pain intensity and unpleasantness without nociception (e.g., additional pain input); (2) This phenomenon may contribute to abnormal pain or other sensory perceptions in these women; (3) Pain anxiety may be an important target for pharmacological and behavioral FM treatments.

Comments: Certainly, one does not have to experience a painful stimulus in the periphery (pin prick, electric shock, etc.) to have blood flow changes (rCBF) in the brain's pain processing centers. "What does this study tell us?" asks Bradley. "It tells us that the anticipation of acute pain in women with FMS who are characterized by a high level of anxiety concerning pain, as well as a predisposition for feelings of depression/anxiety actually may activate pain memories. This can invoke increased pain intensity without actual painful stimulation. Where did we get the idea about pain memory? There was a group of neuroscientists at NIH who did case studies several years ago in which they took patients who had recurrent pain problems and they electrically stimulated the thalamus. The stimulation of the thalamus actually produced activation of the right cingulate cortex and it reproduced the pain ... The cingulate cortex is involved in not only pain, but encoding unpleasant affect or emotionally laden memories." Bradley suspects that similar processes may be going on in FMS patients, contributing to abnormal pain sensitivity and possibly other unusual sensory experiences often described. Plus, if the pain is severe enough to lead to anxiety and depression, then the patient may logically experience even higher levels of pain.

Fatigue and mood disturbances, pain perception and cognition occur frequently in SLE and FMS; their underlying mechanisms, however, remain poorly understood. The pentapeptide corresponding to the last 5 residues of histones H4 (YGFGG) resembles enkephalins (YGGFL, YGGFM) and has enkephalin activity. Thus, the metabolism of endogenous opiates might plausibly be perturbed by some autoAbs (auto-antibodies) that bind the C-terminus of histones H4. Murine sera were screened by ELISA for this binding specificity. IgG autoAbs which bound the C-term of H4 (-GRTYLGFGG) were present in most MRL lpr sera but not in BALB/c, C57B16, C3H, NZBWF1, NZM2410 or gld sera (types of mice). A 20 week old female MRL lpr mouse was used to prepare hybridomas of which 5 (one IgG1, two IgG2a, two IgG3) secreted autoAbs that bound not only the C-term of H4 and intact purified H4 but also -YGGFL. The H4 epitope which these autoAbs bind, however, is not accessible in HEP-2 nuclei in situ in standard IF-ANA assays. These data demonstrate that a subset of anti-histones autoAbs cross react with an important neuropeptide and suggest novel autoimmune mechanisms which might blunt enkephalin dependent responses and distort normal nociception (or pain processing).

Comments: This is a highly technical abstract, but Dr. Fasy's goal was to first screen mice to find out which strain had auto-antibodies present that could interfere with the action of opioids, and then determine if these auto-antibodies could be found in the blood sera of FMS patients. In the mice, Fasy found antibodies that may break down pain fighting molecules called enkephalins. Looking at human FMS sera, Fasy found abnormally high levels of antibodies to nocistatin, a molecule in the enkephalin system which fights pain--so it is bad news to have an antibody that degrades it. The next step is to look at the spinal fluid of FMS patients to uncover more significant abnormalities that may also tie in with the findings in the mouse (making it a potential test model for therapies).

THE ROLE OF ZINC IN FIBROMYALGIA [FMS] PAIN-A PILOT STUDY.
I. Jon Russell, Steven Older, Lawton A Seal, Gerald A. Merrill, Joel E. Michalek, Eleanor Ayala, Gilbert Vipraio, Yoon-Kyoo Kang, Ellen Fletcher, Wanda Haynes, Yolanda Flores, Dana Walters. San Antonio, TX

Background: Zinc deficiency facilitates nociception and allodynia in animals.

Purpose: Seek evidence to implicate zinc in the pathogenesis of fibromyalgia.

Methods: Primary FMS [ACR, N=30) and case-matched [age, gender, ethnicity, education] normal controls [HNC, N=30] were recruited. Power calculations predicted ß=0.8 at a =0.05 with N=27. Usual FMS medications were stopped for two weeks but diets were usual. Plasma zinc [PZ] was drawn at baseline, after 48 hours of single blind, placebo tid and again after 48 hours of single blind, zinc sulfate [60-mg tid] (i.e., administered zinc to determine how much was retained). The primary outcome variables were plasma zinc and three measures of pain severity including the Average Pain Threshold [APT] by dolorimetry. Analyses examined nominal variables by chi-square, continuous variables by T test and linear correlations by the Pearson.

Results: Twenty-nine subjects completed in each group. PZ levels were lower in FMS than in HNC at baseline [P< 0.01] and after placebo Rx. PZ correlated with APT in both groups [r=0.148-0.68]. PZ rose with zinc Rx in FMS [P< 0.02] but did not correct, or increase to normal values. Clinical measures did not improve with zinc Rx.

Conclusions: Zinc is physiologically related to the process of APT in both FMS and HNC. Zinc deficiency may contribute to the allodynia of FMS. Zinc therapy for FMS symptoms cannot yet be recommended with confidence.

Comments: Zinc is an essential mineral in the pain fighting system. This project reports that zinc levels are low in FMS patients, but that supplementation with this mineral did not completely correct the low values. The cause of the zinc deficiency needs to be identified to better determine if and how zinc therapy may help FMS patients.

EXPRESSION OF OPIOID RECEPTORS IN HUMAN MUSCLE AND SKIN TISSUES DETECTED BY REAL TIME PCR.
Souzan Salemi, Laurence Bradley, Graciela Alarcon, Shin J. Oh, Uwe Wollina, Jamine Rethage, Frank Heppner, Renate E. Gay, Steffen Gay, and Haiko Sprott. Zurich, Switzerland.

Delta, Kappa and Mu opioid receptors are widely expressed in the central nervous system (CNS). Recent data suggest that opioid antinociception can be initiated by activation of opioid receptors outside the CNS (Bigliardi-Qi M et al, J Invest Dermatol 114:527-32, 2000). Therefore, we investigated the expression of opioid receptor mRNA in skin and muscle tissues of healthy volunteers by molecular methods to search for their presence.

Healthy women were recruited from the Divi of Clinical Immunology and Rheumatology, Univ of Alabama at Birmingham (muscle biopsies) and the Dept of Derm Allergol, Univ Jena (skin biopsies). Snap frozen sections from 10 skin samples (mean age of women 46.6±2.5 years) and sections from 9 muscle samples (mean age of women 45.0±4.4 years) were obtained from the left deltoid region. Normal brain tissue of an age-matched woman was used as positive control. Total RNA isolated from the tissue samples was reverse transcribed, amplified and quantitated by real time PCR (TaqMan, Perkin Elmer) using designed opioid receptor fluorogenic probes and specific primers for each. Expression intensity of each tissue was calculated with the expression of 18S (internal control).

All muscle and skin tissue samples examined expressed detectable levels of Delta and Kappa opioid receptor. The Delta receptor in the skin was 68.5 fold and the Kappa receptor 97.0 fold more expressed than in brain tissue. The Delta receptor was 43.7 fold in the muscle and the Kappa receptor 1.6 fold less expressed than in brain tissue. Mu opioid receptor mRNA was expressed in normal brain but not in healthy control skin and muscle.

These results are consistent with our hypothesis that opioid receptors are expressed in the skin and muscle of health women. Here, for the first time, we have demonstrated the existence of Delta and Kappa opioid receptors in these tissues outside the CNS. These results offer the opportunity to study the function of these receptors in pain in both sexes as well as in different chronic pain diseases.

Comments: The purpose of this study was to demonstrate that opioid receptors (specifically Delta and Kappa) are highly populated in the skin tissues. Traditionally, opioid receptors have been thought to reside in the central nervous system only (i.e., the brain and spinal cord) and that pain therapies would have to target the CNS. Yet, if this data holds up, then it may be possible to relieve the pain of FMS by applying a topical cream or gel to the skin that works on the Delta and/or Kappa opioid pain receptors. This type of treatment could be virtually free of side effects!

EXPRESSION OF OPIOID RECEPTOR OR VARIANTS IN SKIN AND MUSCLE TISSUE OF FIBROMYALGIA (FM) PATIENTS.
Souzan Salemi, Lorenzo Kaeser, Laurence Bradley, Graciela S. Alarcon, Shin J. Oh, Uwe Wollina, Janine Rethage, Frank Heppner, Renate E Gay, Steffen Gay, Haiko Sprott Zurich, Switzerland;Birmingham, AL;Jena, Germany and Zurich,Switzerland

FM is a syndrome characterized by widespread musculoskeletal pain. The opioid system plays a major role in pain regulation. It consists of a family of endogenous peptides. There are at least three OR types: Delta (DOR), Kappa (KOR), and Mu OR (MOR). OR expression in skin and muscle from FM patients may be abnormal (persistent pain, inadequate treatments) compared to controls.

FM-patients (8 women, 30-65 years) were recruited from the Univ Hosp Zurich. Healthy age and gender matched controls for muscle biopsy (n=9) were recruited from the Univ Alabama, Birmingham and for skin biopsy (n=10) from the Univ Jena. Biopsies were obtained from the left deltoid region. One normal brain tissue was used as a positive control. Total RNA isolated from the tissue samples were reverse transcribed, amplified and quantitated by real time PCR (TaqMan, Perkin Elmer) using OR fluorogenic probes and specific primers for each OR. Expression intensity of each tissue was calculated with the 18S expression (internal control).

We observed 116.9 fold DOR and 20.67 fold increase of KOR mRNA expression in skin samples and 168.8 fold DOR and 445.7 fold KOR increase in muscle samples of FM patients compared to brain control tissue. The expression levels of DOR 81.0 fold (p=0.001) and KOR 13.6 fold (p=0.009) mRNA in FM skin were significantly increased compared to that of healthy controls (Mann-Whitney test). No significant differences could be detected in muscle tissues. MOR mRNA was only expressed in normal brain (positive control).

Recent data suggested that opioid antinonciception can be initiated by activation of OR present outside of the central nervous system (Bigliardi-Qi M et al, J invest Dermatol 114:527-32,2000). We demonstrated that DOR and KOR were more expressed in the skin of female FM patients which could be the result of severe and persistent pain. The increased levels of the OR despite the persistent pain does not result in analgesia. The present results may provide novel insights for topical pain treatment with selected opioids.

Comments: These findings are only preliminary, in that 25 subjects will eventually be tested and compared to healthy controls. The purpose is to identify if there are certain opioid receptor types that are more or less prevalent in the skin and muscle of patients, compared to controls. Preliminary data show that the Kappa and Delta receptors are many-fold increased in the tissues. What makes this finding so interesting is that most opioid medications operate primarily on the Mu opioid receptor site, and only exert minimal action on the Kappa and Delta sites. In fact, there is no Delta-selective drug available and Dr. Sprott speculates that it could be the opioid drug of choice for treating FMS (topically or orally). If the data holds up upon expansion to a larger number of patients, then the next logical step would be do develop a topical opioid drug that is selective for the Delta and possibly the Kappa sites in the tissues. In this fashion, application of a drug in the periphery might tame the central nervous system pain. The same would hold true for oral administration.

CYTOKINES PLAY AN ETIOPATHOGENETIC ROLE IN FIBROMYALGIA: A PILOT STUDY.
Daniel J. Wallace, Mariana Linker-Israeli, David Hallegua, Stuart Silverman, David Silver, Michael H Weisman. Los Angeles, CA

Fibromyalgia (FM) is felt to be a syndrome characterized by abnormal processing of pain signals which arises from a combination of stress and behavioral constructs interacting with neurotransmitters, hormones, cytokines, and the sympathetic nervous system. We examined cytokine expression in FM. 56 FM patients and 36 age-sex-matched controls were studied. Mean age 50.4 years, 92.9% females. 26 had symptoms for > 2 years. Cytokines and cytokine-related molecules were measured in sera and in supernatants of peripheral blood mononuclear cells (PBMC) that were incubated with and without lectins and PMA.

Results: No differences between FM and controls were found by measuring IL-1, IL-10, sIL-2r, IFN-g, TNF-a. IL-1 Ra (p=0.002) and IL-8 (p=0.01) levels were significantly higher in sera and IL-1 Ra and IL-6 in stimulated and unstimulated FM PBMC compared to controls (p=0.05). Serum IL-6 levels were comparable to controls, but were elevated in supernatants of in vitro activated PBMC derived from patients with < 2 years of symptoms (p=0.01). In the presence of PMA, there was an additional increase of IL-1Ra, IL-8, and IL-6 over control values (p<0.05).

Conclusion: Soluble factors whose release is stimulated by substance P were found to be increased in FM patients, possibly, related in part to symptom duration. Since IL-8 promotes sympathetic pain and IL-6 induces hyperalgesia, it is hypothesized that they may play a role in modulating FM symptoms.

Comments: This study provides the first documented link between the immune system and the pain control system. In addition, the longer a person has FMS, the greater their chances are of having increased cytokine abnormalities, especially IL-8 and IL-6.